Association of Peripheral Blood Biomarkers with Response to anti-PD-1 Immunotherapy for Patients with dMMR Metastatic Colorectal Cancer: A Multicenter Cohort Study

Abstract

Background: Mismatch repair deficient (dMMR) is an established biomarker for response to anti-PD-1 immunotherapy in metastatic colorectal carcinoma (mCRC). Although patients with dMMR mCRC could achieve a high incidence of disease control and favorable progression-free survival (PFS), reported response rates to PD-1 inhibitors are variable with 28%–52%, indicating that additional predictive biomarkers are warranted. \n \nMethods: This multicenter cohort study enrolled patients with dMMR mCRC receiving anti-PD-1 immunotherapy at Sun Yat-sen University, the Sixth Affiliated Hospital and Sun Yat-sen University Cancer Center between December, 2016 to December, 2019. A total of 20 peripheral blood biomarkers, including T cells (CD4+ T cell, CD8+ T cell, ratio of CD4+/CD8+), carcinoembryonic antigen (CEA), inflammatory markers and lipid metabolism markers. The association between response or survival and peripheral blood parameters was analyzed. \n \nResults: Among tested parameters, ratio of CD4+/CD8+, CD4+ T cell was significantly associated with PFS (P=0.023, P=0.012) and OS (P=0.027, P=0.019) in univariate analysis. Lower level of CD4+/CD8+ ratio or CD4+ T cell showed significant association with better overall response rates (ORR; P = 0.03, P=0.01). Ratio of CD4+/CD8+, and CD4+ T cell maintained significance in multivariate Cox model for PFS (HR=9.23, P=0.004; HR=4.83, P=0.02) and OS (HR=15.22, P=0.009; HR=16.21, P=0.025). \n \nConclusions: Ratio of CD4+/CD8+ and CD4+ T cell might be crucial independent biomarkers within dMMR mCRC to better identify patients for response to PD-1 inhibitors. If validated in prospective clinical trials, ratio of CD4+/CD8+ and CD4+ T cell might provide aid in guiding the treatment of PD-1 inhibitors in dMMR mCRC. \n \nFunding Statement: This study was supported by The National Key Research and Development Program of \nChina (N0.2017YFC1308800), National Natural Science Foundation of China (Grant No. 81703060, 81802441), China Postdoctoral Science Foundation funded project (Grant No. 2018T110911), Science and Technology Planning Project of Guangzhou (No. 201902020009), Key-Area Research and Development Program of Guangdong Province (2019B020229002), Sun Yat-sen University 5010 Project (NO. 2010012), Sun Yat-sen University Young Teacher Training Program (NO. 20ykpy12), Science and Technology Planning Project of Guangdong (2017A030310644), and National Key Clinical Discipline. \n \nDeclaration of Interests: We declare no potential conflicts of interest. \n \nEthics Approval Statement: This study was approved by the ethics review board of the Sixth Affiliated Hospital, Sun Yat-Sen University. Written informed consent from patients was waived due to the retrospective nature of our study.